WO2016138099A1 - Utilisation de ghréline ou d'agonistes fonctionnels des récepteurs de la ghréline pour prévenir et traiter une maladie psychiatrique sensible au stress - Google Patents

Utilisation de ghréline ou d'agonistes fonctionnels des récepteurs de la ghréline pour prévenir et traiter une maladie psychiatrique sensible au stress Download PDF

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WO2016138099A1
WO2016138099A1 PCT/US2016/019297 US2016019297W WO2016138099A1 WO 2016138099 A1 WO2016138099 A1 WO 2016138099A1 US 2016019297 W US2016019297 W US 2016019297W WO 2016138099 A1 WO2016138099 A1 WO 2016138099A1
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ghrelin
subject
memory
stress
agent
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Ki Ann GOOSENS
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Massachusetts Institute Of Technology
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/54—Determining the risk of relapse

Definitions

  • the present disclosure provides several surprising findings. For instance, in unstressed subjects, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala. Higher levels of ghrelin after a traumatic exposure, as well as pharmacological agonism of the ghrelin receptor during the memory consolidation period following the traumatic exposure, decrease long-term fear memory strength.
  • the invention is based, at least in part, on the surprising findings that a subject who has been exposed to trauma can be administered ghrelin or a functional ghrelin receptor agonist during the memory consolidation period or following re-activation of the memory (during reconsolidation) of a traumatic experience can reduce consolidation or reconsolidation of the memory, and reduce the impact of the trauma on stress-sensitive mental disorders. Further provided herein is the novel finding that chronic stress induces a persistent resistance to ghrelin, mediated by long-term downregulation of its receptor in the brain. Accordingly, the new link between stress, a novel type of metabolic ghrelin resistance, and vulnerability to excessive fear memory formation affords opportunity for formulating new therapeutics for stress-sensitive psychiatric disorders.
  • the memory consolidation period is 0 hours - 1 week, 0 hours-5 days, 0 hours - 48 hours, or 0-24 hours following the trauma exposure. In some embodiments the memory consolidation period is 0-6 hours following the trauma exposure. In some embodiments the memory consolidation period is 0-1 hour following the trauma exposure.
  • ghrelin is administered to the subject.
  • the ghrelin is in the form of acyl-ghrelin.
  • the agent targets the ghrelin receptor (GHSR).
  • GHSR ghrelin receptor
  • the agent is a functional GHSR agonist.
  • the functional GHSR agonist may be: Adenosine, alexamorelin, Anamorelin, Capromorelin, CP-464709, Cortistatin-14, Examorelin (hexarelin), Growth Hormone Releasing Peptide -1 (GHRP-1), Growth Hormone Releasing Peptide -2 (GHRP-2), Growth Hormone Releasing Peptide -3 (GHRP-3), Growth Hormone Releasing Peptide -4 (GHRP-4), Growth Hormone
  • the functional ghrelin receptor agonist is ibutamoren mesylate (IBU).
  • the agent is a compound that enhances or facilitates the synthesis or release of ghrelin from the stomach. In some embodiments, the agent is a compound that enhances or facilitates the acylation of ghrelin.
  • the agent is a compound that reduces or decreases the de- acylation or breakdown of ghrelin.
  • a therapeutically effective amount of ghrelin and the agent that enhances ghrelin signaling is administered.
  • administering is via systemic administration, injection, or infusion directly into the BLA of the subject.
  • the stress-sensitive psychiatric disease is selected from the group consisting of: Post-traumatic Stress Disorder (PTSD), Depressive Disorder, Major Depressive Disorders, Post-partum Depression, Bipolar Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Obsessive-Compulsive Disorder, Panic Disorders, Schizophrenia, and Trichotillomania.
  • Post-traumatic Stress Disorder PTSD
  • Depressive Disorder Major Depressive Disorders
  • Post-partum Depression Post-partum Depression
  • Bipolar Disorder Bipolar Disorder
  • Acute Stress Disorder Generalized Anxiety Disorder
  • Obsessive-Compulsive Disorder Panic Disorders
  • Schizophrenia Trichotillomania
  • ghrelin or an agent that enhances ghrelin signaling in the basolateral complex of the amygdala (BLA), within a memory re-consolidation period following re-activation of a memory of a previous trauma exposure.
  • the memory re-consolidation period is 0 hours - 1 week, 0 hours- 5 days, 0 hours - 48 hours, or 0-24 hours following the re-activation of a memory of a previous trauma exposure. In some embodiments, the memory re-consolidation period is 0-6 hours following the re-activation of a memory of a previous trauma exposure. In some embodiments, the memory re-consolidation period is 0- 1 hour following the re-activation of a memory of a previous trauma exposure.
  • ghrelin is administered to the subject.
  • the ghrelin is in the form of acyl-ghrelin.
  • the agent targets the ghrelin receptor (GHSR).
  • the agent is a functional GHSR agonist.
  • the functional ghrelin receptor agonist may be: Adenosine, alexamorelin, Anamorelin, Capromorelin, CP-464709, Cortistatin-14, Examorelin (hexarelin), Growth Hormone Releasing Peptide -1 (GHRP-1), Growth Hormone Releasing Peptide -2 (GHRP-2), Growth Hormone Releasing Peptide -3 (GHRP-3), Growth Hormone Releasing Peptide -4 (GHRP-4), Growth Hormone Releasing Peptide - 5 (GHRP-5), Growth Hormone Releasing Peptide -6 (GHRP-6), Ibutamoren (MK- 677), Ibutamoren mesylate (IBU), Ipamorelin, L-692585, LY-426410, LY-444711,
  • the functional ghrelin receptor agonist is ibutamoren mesylate (IBU).
  • control is a subject not exposed to chronic stress. In some embodiments, the subject is a human.
  • FIGs. 1A-E show post-conditioning acyl-ghrelin levels are a negative predictor of long- term fear memory strength.
  • FIG. 1A shows the experimental design.
  • FIG. 1C shows the best fit plane from a regularized linear regression, using the Lasso method, of freezing (%) predicted by ghrelin levels after fear conditioning. The best fit plane is shown in gray; each point represents one rat.
  • FIG. IE shows a cumulative percentage plot for risk assessment behavior in individual rats during the long-term auditory fear recall test. Error bars represent +SEM; *p ⁇ 0.05, *** p ⁇ .001, ****p ⁇ 0.0001.
  • FIG. 3C shows the systemic administration of IBU at the dose used in experiment described in FIG. 3A (0.5 mg/mL) does not impact food consumption either shortly following injection (left panel;
  • FIGs. 4A-F show chronic stress decreases ghrelin binding in the amygdala and renders animals insensitive to the fear-reducing effects of a ghrelin receptor agonist.
  • FIG. 4A shows the experimental design of FIG. 4B.
  • FIG. 4B shows the representative confocal images (20X) of biotinylated ghrelin binding (gray puncta) in the BLA of an unstressed (NS) or chronically stressed (STR) rat.
  • Gray signal represents nuclear DAPI staining.
  • White arrowheads indicate representative ghrelin binding in cell bodies. Gray arrowheads point to staining present in the inter-neuronal cell body spaces.
  • FIGs. 6A-B shows iterations of the Lasso technique.
  • mean squared error MSE
  • Lambda is the regularization constant for the algorithm; as lambda increases, the regression is more regularized, such that the algorithm penalizes over- fitting more heavily and the resulting model is more likely to generalize to independent data sets.
  • the rightmost dotted line indicates the value of lambda with the minimum MSE for predicting freezing.
  • the blood-brain barrier is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid (BECF) in the central nervous system (CNS).
  • BECF brain extracellular fluid
  • CNS central nervous system
  • the blood-brain barrier is formed by brain endothelial cells, which are connected by tight junctions with an extremely high electrical resistivity of at least 0.1 ⁇ -m.
  • the blood-brain barrier allows the passage of water, some gases, and lipid-soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function.
  • the blood-brain barrier may prevent the entry of lipophilic, potential neurotoxins by way of an active transport mechanism mediated by P-glycoprotein.
  • LTP long-term potentiation
  • Memory encoding and consolidation contributes to the formation of traumatic memories in humans following an experience that causes high levels of emotional arousal and the activation of stress hormones.
  • the strength of the traumatic memories experienced by an individual has severe biological and psycho-social impact and may trigger stress-sensitive psychiatric diseases.
  • enhanced consolidation, or "over-consolidation" of fearful memories is thought to underlie the development of some trauma and stress-related disorders such as post-traumatic stress disorder (PTSD), interventions that reduce the consolidation of fear memories represent a promising strategy to prevent the development of these disorders.
  • PTSD post-traumatic stress disorder
  • activation maybe used interchangeably in the present disclosure when they related accessing the information stored in a long-term memory. Any means to retrieve or reactive a long-term memory that is well-known by those skilled in the art, e.g., hypnosis, maybe used in accordance with the present disclosure.
  • GHSRs are also expressed in other brain regions not traditionally associated with feeding behavior, such as the basolateral complex of the amygdala (BLA), a brain region important for regulating fear.
  • BLA amygdala
  • the abundance of GHSR in the BLA suggests that ghrelin signaling modulates fear, but the role of acyl-ghrelin in BLA-dependent fear memory has remained controversial. While some groups report that transient elevation of ghrelin signaling promotes the excitability of BLA neurons 8 , others find that ghrelin decreases BLA excitability 6 . Disclosed herein is the role of endogenous acyl-ghrelin in BLA-dependent fear memory formation.
  • ghrelin or the agent When ghrelin or the agent is administered before the exposure to trauma or the reactivation of a previous traumatic memory, they need to be administered at a time close enough to the onset of the traumatic exposure, e.g. , a military operation, so that when the traumatic exposure occurs, the subject is protected from over-consolidation of the traumatic memory by the elevated ghrelin signaling.
  • aspects of the present disclosure are based, in part, on the surprising finding that, basal acyl-ghrelin levels in unstressed subjects are strongly and negatively associated with long- term fear memory formation (as illustrated in FIG. 2B).
  • some aspects of the present disclosure relate to determining whether a subject has an increased/reduced risk of developing a stress-sensitive psychiatric disease following a traumatic exposure. For example, if elevated basal levels of ghrelin are detected in the subject, the subject may be considered to be at lower risk of developing a stress-sensitive psychiatric disease following exposure to trauma.
  • Levels of ghrelin can be measured according to any assay familiar to one of ordinary skill in the art. For example, levels of ghrelin could be measured by a Western blot or an ELISA. In some embodiments, an assay to measure ghrelin levels is conducted on a blood sample.
  • the level of ghrelin in a subject is compared to a control level. It should be appreciated that the appropriate control will vary depending on the circumstances.
  • the control level can be the level of ghrelin in a subject who has not been exposed to chronic stress.
  • a stressed subject has prolonged elevated levels of ghrelin. It is to be understood, based on the ghrelin resistance mechanism described in the present disclosure, a subject who has been exposed to chronic stress and who shows an elevated endogenous level of ghrelin, also has reduced GHSR expression level in the BLA and is insensitive to the inhibitory effect of ghrelin in reducing fear memory consolidation. In some embodiments, such subject may be considered a subject who has an increased risk of developing a stress-sensitive disorder following a traumatic exposure.
  • the first agent may be administered to the subject for a period of time long enough to achieve the upregulation.
  • the first agent may be administered for 1 week to 24 months, or longer.
  • the first agent is administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months.
  • Endogenous ghrelin levels may be measured at multiple time points during the time period when the first agent is administered.
  • a reduction in endogenous ghrelin levels is interpreted herein that the GHSR levels would increase correspondingly. It is to be understood that it may take time for GHSR levels to rise after a reduction endogenous ghrelin level is observed and that the first agent should continue to be administered following the first observation of reduction in the endogenous ghrelin level in the stressed subject.
  • Other aspects of the methods relate to treating stress- sensitive psychiatric diseases following a traumatic exposure in the stressed subject, wherein the subject has been
  • a therapeutically effective amount of a second agent that enhances ghrelin signaling is administered.
  • the second agent targets ghrelin receptor (GHSR).
  • GHSR ghrelin receptor
  • the agent may be a functional GHSR agonist.
  • a functional ghrelin receptor agonist refers to a substance or a compound that binds to and activates GHSRs to produce a biological response that mimics ghrelin signaling.
  • the functional ghrelin agonist can be an agent that has been developed to activate ghrelin signaling in other contexts, such as to combat cachexia (loss of appetite, often observed in humans with other illnesses like cancer) or muscle loss (observed in aging humans).
  • agents that activate ghrelin signaling include: Adenosine, alexamorelin , Anamorelin from Helsinn Therapeutics, Capromorelin from Pfizer inc., CP-464709 from Pfizer Inc., Cortistatin-14, Examorelin (hexarelin) from Mediolanum Farmaceutici, Growth Hormone Releasing Peptide -1 (GHRP-1), Growth Hormone Releasing Peptide -3 (GHRP-3), Growth Hormone Releasing Peptide -4 (GHRP-4), Growth Hormone Releasing Peptide - 5 (GHRP-5), Growth Hormone Releasing Peptide -6 (GHRP-6), Ibutamoren (MK-677) from Reverse Pharmacology, Ibutamoren mesylate (IBU), Ipamorelin from Helsinn Therapeutics, L-692,585, LY-426410 from Eli Lily, LY-44
  • both ghrelin and the second agent that enhances ghrelin signaling may be administered concurrently. It is also to be understood that the agents disclosed herein for enhancing ghrelin signaling maybe administered individually or in any combination thereof, so as to achieve the desired potency of ghrelin signaling activation.
  • Enhance means the magnitude of ghrelin signaling in the subject increases after the subject is administered a therapeutically effective amount of the agent, e.g. , a ghrelin agonist, compared to before the administration of the agent.
  • ghrelin signaling maybe completely lacking before the agent is administered and administering a therapeutically effective amount of the agent activates results in the presence of ghrelin signaling. In such instances, it is also considered that the agent has "enhanced" ghrelin signaling.
  • the ghrelin or the second agent can be administered to a subject before, during and/or after the traumatic exposure.
  • ghrelin or the second agent can be administered to a subject in anticipation of exposure to trauma, such as prior to participation in a military operation.
  • ghrelin or the agent can protect against the consequences of exposure to trauma.
  • Ghrelin or the agent can also be administered to a subject during exposure to trauma to protect against the consequences of exposure to trauma and treat symptoms associated with the effects of trauma.
  • Ghrelin or the agent can also be administered after exposure to trauma to protect against the consequences of exposure to trauma and treat symptoms associated with the effects of trauma.
  • ghrelin agonists are not addictive and therefore potentially represent a less risky and more promising intervention in trauma-exposed humans at risk for PTSD.
  • a history of stress exposure promotes ghrelin resistance in the amygdala.
  • higher doses of GABA receptor agonists or ghrelin may be required to achieve therapeutic efficacy in fear memory reduction.
  • the non-addictive ghrelin or ghrelin agonists are much more suitable than GABA receptor agonists.
  • treatment refers to both therapeutic and prophylactic treatments. If the subject in need of treatment is experiencing a condition (i.e., has or is having a particular condition), then “treating the condition” refers to ameliorating, reducing or eliminating one or more symptoms associated with the disorder or the severity of the disease or preventing any further progression of the disease. If the subject in need of treatment is one who is at risk of having a condition, then treating the subject refers to reducing the risk of the subject having the condition or preventing the subject from developing the condition.
  • a subject shall mean a human or vertebrate animal or mammal including but not limited to a dog, cat, horse, cow, pig, sheep, goat, turkey, chicken, and primate, e.g. , monkey.
  • the methods of the present disclosure are useful for treating a subject in need thereof.
  • a subject in need thereof can be a subject who will be exposed to trauma, is currently exposed to trauma or has been exposed to trauma.
  • a subject in need thereof may be a subject involved, or who will be involved, in a military operation or combat mission.
  • a subject in need thereof can be a subject having or at risk of a stress-sensitive psychiatric disease.
  • a subject can be a patient who is diagnosed with a stress-sensitive psychiatric disease, or a subject with a strong familial history of such disorders.
  • Therapeutic compounds or agents e.g. , ghrelin or functional ghrelin agonists and other compounds that enhance ghrelin signaling, or reversal of ghrelin resistance associated with the present disclosure may be directly administered to the subject or may be administered in conjunction with a delivery device or vehicle. Delivery vehicles or delivery devices for delivering therapeutic compounds to surfaces have been described. The therapeutic compounds of the present disclosure may be administered alone (e.g. , in saline or buffer) or using any delivery vehicles known in the art.
  • terapéuticaally effective amount refers to the amount necessary or sufficient to realize a desired biologic effect. For example,
  • therapeutically effective amount of a ghrelin agonist associated with the present disclosure may be that amount sufficient to ameliorate one or more symptoms of a stress-sensitive psychiatric disease in a subject who has had a traumatic exposure.
  • an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial toxicity and yet is entirely effective to treat the particular subject.
  • the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular therapeutic compounds being
  • Subject doses of the compounds described herein for delivery typically range from about 0.1 ⁇ g to 10 mg per administration, which depending on the application could be given daily, weekly, or monthly and any other amount of time there between.
  • a single dose is administered during the critical consolidation or reconsolidation period.
  • the doses for these purposes may range from about 10 ⁇ g to 5 mg per administration, and most typically from about 100 ⁇ g to 1 mg, with 2 - 4 administrations being spaced days or weeks apart.
  • parenteral doses for these purposes may be used in a range of 5 to 10,000 times higher than the typical doses described above.
  • a compound of the present disclosure is administered at a dosage of between about 1 and 10 mg/kg of body weight of the mammal. In other embodiments a compound of the present disclosure is administered at a dosage of between about 0.001 and 1 mg/kg of body weight of the mammal. In yet other embodiments a compound of the present disclosure is administered at a dosage of between about 10 - 100 ng/kg, 100-500 ng/kg, 500 ng/kg- 1 mg/kg, or 1 - 5 mg/kg of body weight of the mammal, or any individual dosage therein.
  • compositions of the present disclosure are administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients.
  • an effective amount of the therapeutic compound associated with the present disclosure can be administered to a subject by any mode that delivers the therapeutic agent or compound to the desired surface, e.g. , mucosal, systemic.
  • Administering the therapeutic agent or compound to the desired surface e.g. , mucosal, systemic.
  • composition of the present disclosure may be accomplished by any means known to the skilled artisan.
  • Preferred routes of administration include but are not limited to oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, rectal and intracerebroventricular.
  • a therapeutically effective amount of ghrelin or an agent that enhances ghrelin signaling maybe infused directly to the basolateral complex of the amygdala (BLA) of the subject.
  • the therapeutic compounds of the present disclosure can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the present disclosure to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral formulations may also be formulated in saline or buffers, i.e., EDTA for neutralizing internal acid conditions or may be administered without any carriers.
  • oral dosage forms of the above component or components may be chemically modified so that oral delivery of the derivative is efficacious.
  • the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of proteolysis; and (b) uptake into the blood stream from the stomach or intestine.
  • the increase in overall stability of the component or components and increase in circulation time in the body is also desired.
  • moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline (Abuchowski and Davis, 1981, “Soluble Polymer-Enzyme Adducts” In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383; Newmark, et al., 1982, J. Appl. Biochem. 4: 185-189).
  • Other polymers that could be used are poly-1,3- dioxolane and poly-l,3,6-tioxocane.
  • Preferred for pharmaceutical usage, as indicated above, are polyethylene glycol moieties.
  • the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
  • One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine.
  • the release will avoid the deleterious effects of the stomach environment, either by protection of the therapeutic agent or by release of the biologically active material beyond the stomach environment, such as in the intestine.
  • a coating impermeable to at least pH 5.0 is preferred.
  • cellulose acetate trimellitate hydroxypropylmethylcellulose phthalate
  • HPMCP 50 hydroxypropylmethylcellulose phthalate
  • HPMCP 55 polyvinyl acetate phthalate
  • PVAP polyvinyl acetate phthalate
  • Eudragit L30D Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac.
  • CAP cellulose acetate phthalate
  • Shellac Shellac
  • a coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow.
  • Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic i.e., powder; for liquid forms, a soft gelatin shell may be used.
  • the shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.
  • the therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm.
  • the formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets.
  • the therapeutic could be prepared by compression.
  • Colorants and flavoring agents may all be included.
  • the therapeutic agent may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.
  • diluents could include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch.
  • Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride.
  • Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.
  • Disintegrants may be included in the formulation of the therapeutic into a solid dosage form.
  • Materials used as disintegrates include but are not limited to starch, including the
  • disintegrant based on starch, Explotab.
  • Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used.
  • Another form of the disintegrants are the insoluble cationic exchange resins.
  • Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.
  • Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin.
  • MC methyl cellulose
  • EC ethyl cellulose
  • CMC carboxymethyl cellulose
  • PVP polyvinyl pyrrolidone
  • HPMC hydroxypropylmethyl cellulose
  • Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes.
  • stearic acid including its magnesium and calcium salts
  • PTFE polytetrafluoroethylene
  • Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.
  • the glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.
  • surfactant might be added as a wetting agent.
  • Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfo succinate and dioctyl sodium sulfonate.
  • anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfo succinate and dioctyl sodium sulfonate.
  • Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride.
  • non-ionic detergents that could be included in the formulation as surfactants are lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the therapeutic agent either alone or as a mixture in different ratios.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. ,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • pulmonary delivery of the therapeutic compounds of the present disclosure is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream.
  • inhaled molecules include Adjei et al., 1990, Pharmaceutical Research, 7:565-569; Adjei et al., 1990, International Journal of Pharmaceutics, 63: 135-144 (leuprolide acetate); Braquet et al., 1989, Journal of
  • Contemplated for use in the practice of this present disclosure are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
  • Ultravent nebulizer manufactured by Mallinckrodt, Inc.
  • each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, and/or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated.
  • Chemically modified therapeutic agent may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.
  • Formulations suitable for use with a nebulizer will typically comprise therapeutic agent dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound per mL of solution.
  • the formulation may also include a buffer and a simple sugar (e.g. , for stabilization and regulation of osmotic pressure).
  • the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound caused by atomization of the solution in forming the aerosol.
  • Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the therapeutic agent suspended in a propellant with the aid of a surfactant.
  • the propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and
  • Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.
  • Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing therapeutic agent and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation.
  • the therapeutic agent should most advantageously be prepared in particulate form with an average particle size of less than 10 mm (or microns), most preferably 0.5 to 5 mm, for most effective delivery to the distal lung.
  • Intra-nasal delivery of a pharmaceutical composition of the present disclosure is also contemplated. Intra-nasal delivery allows the passage of a pharmaceutical composition of the present disclosure to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung.
  • Formulations for nasal delivery include those with dextran or cyclodextran.
  • a useful device is a small, hard bottle to which a metered dose sprayer is attached.
  • the metered dose is delivered by drawing the pharmaceutical composition of the present disclosure solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed.
  • the chamber is compressed to administer the pharmaceutical composition of the present disclosure.
  • the chamber is a piston arrangement.
  • Such devices are commercially available.
  • a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used.
  • the opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation.
  • the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.
  • agents when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g. , by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. , in ampoules or in multi- dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active compounds may be in powder form for constitution with a suitable vehicle, e.g. , sterile pyrogen-free water, before use.
  • a suitable vehicle e.g. , sterile pyrogen-free water
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation.
  • Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin.
  • the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as
  • compositions are suitable for use in a variety of drug delivery systems.
  • Langer Science 249: 1527-1533, 1990, which is incorporated herein by reference.
  • the therapeutic compounds of the present disclosure and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt.
  • the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof.
  • Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
  • salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
  • Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v).
  • Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3- 0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% w/v).
  • compositions of the present disclosure contain an effective amount of a therapeutic compound of the present disclosure optionally included in a pharmaceutically- acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present disclosure, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
  • the therapeutic agents may be delivered to the brain using a formulation capable of delivering a therapeutic agent across the blood brain barrier.
  • a formulation capable of delivering therapeutics to the brain is the physiology and structure of the brain.
  • the blood-brain barrier is made up of specialized capillaries lined with a single layer of endothelial cells. The region between cells are sealed with a tight junction, so the only access to the brain from the blood is through the endothelial cells.
  • the barrier allows only certain substances, such as lipophilic molecules through and keeps other harmful compounds and pathogens out. Thus, lipophilic carriers are useful for delivering non-lipophilic compounds to the brain.
  • DHA a fatty acid naturally occurring in the human brain has been found to be useful for delivering drugs covalently attached thereto to the brain (Such as those described in US Patent 6407137).
  • US Patent 5,525,727 describes a dihydropyridine pyridinium salt carrier redox system for the specific and sustained delivery of drug species to the brain.
  • US Patent 5,618,803 describes targeted drug delivery with phosphonate derivatives.
  • US Patent 7119074 describes amphiphilic prodrugs of a therapeutic compound conjugated to an PEG-oligomer/polymer for delivering the compound across the blood brain barrier. Others are known to those of skill in the art.
  • the therapeutic agents of the present disclosure may be delivered with other therapeutics for treating stress-sensitive psychiatric diseases.
  • the following examples are provided to illustrate specific instances of the practice of the present disclosure and are not intended to limit the scope of the present disclosure. As will be apparent to one of ordinary skill in the art, the present disclosure will find application in a variety of compositions and methods.
  • ghrelin can be used to protect humans from stress-sensitive diseases involving excessive negative affect, and also to treat such diseases.
  • diseases include, but are not limited to, Post-traumatic Stress Disorder (PTSD), Depressive Disorder, Major Depressive Disorders, Bipolar Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Obsessive-Compulsive Disorder, Panic Disorders, Schizophrenia and Trichotillomania.
  • PTSD Post-traumatic Stress Disorder
  • Depressive Disorder Depressive Disorder
  • Major Depressive Disorders Bipolar Disorder
  • Acute Stress Disorder Generalized Anxiety Disorder
  • Obsessive-Compulsive Disorder Panic Disorders
  • Schizophrenia Trichotillomania.
  • the invention provides a method to reduce the consolidation of emotional memories during trauma or stress exposure to reduce the development of stress- sensitive mental illnesses.
  • the method comprises administration of a therapeutically effective amount of either ghrelin or a functional ghrelin receptor agonist to humans shortly (immediately to one day) following trauma exposure in order to prevent the development of stress- sensitive mental disorders.
  • ghrelin or a functional ghrelin receptor agonist may be administered shortly following re-activation of the memory of a traumatic experience to reduce reconsolidation of the memory, and reduce the impact of the trauma on stress-sensitive mental disorders.
  • chronic stress which is a risk factor for developing mental illness, produces this vulnerability, in part, by producing ghrelin resistance.
  • Individuals who have a high stress "load" may benefit from higher doses of compounds to achieve therapeutic effects and/or treatment with an agent that reduces ghrelin resistance.
  • IBU ibutamoren mesylate
  • rats were injected with 1 ml kg "1 intraperitoneal injection (i.p.) of either vehicle or drug.
  • Ibutamoren mesylate (Axon Medchem, Groningen, The Netherlands) is a specific GHSRla agonist with a half-life of >6 h and readily crosses the blood-brain barrier 46 .
  • a concentration of 0.5 mg ml "1 diluted in saline, was used.
  • Surgical Procedures Some rats received externalized jugular vein catheters or bilateral intra-BLA cannulae. Some rats were purchased from a commercial supplier with externalized jugular vein catheter implants. Catheters were flushed with sterile saline (0.1 cc) every other day until fear conditioning commenced. Sterile heparin lock solution was infused after the saline flush to maintain the patency of the catheter.
  • Dummy cannulae extending 1 mm past the tip of the guide cannulae were placed into the guide cannula after surgery and changed every other day.
  • mice had blood samples collected Samples were placed in tubes on ice until they were spun (2100 g, 4°C, 10 minutes). The supernatant (plasma) was placed in new tubes. For analysis of acylated ghreiin, 60 ⁇ was placed in a tube containing 3 ⁇ of 0.5M HQ. For analysis of coiticosterone, 15 ⁇ was placed in another tube. The remainder was placed in a third tube. All tubes were stored at -80°C until analysis.
  • Rats with jugular catheters were gently restrained while the catheter plug was removed.
  • HALT cocktail (Thermo Scientific/Rockford, IL). Each catheter was flushed with sterile saline (-0.15 cc) and 0.05 cc of sterile heparin lock solution was injected into the catheter. Sterile catheter plugs were reinserted.
  • Some rats were subjected to auditory Pavlovian fear conditioning and extinction testing, a food consumption assay, or chronic immobilization stress.
  • a subset of rats were subjected to auditory Pavlovian fear conditioning and extinction testing. All rats were transported in their home cages from the vivarium to a holding room, in which no behavioral testing was conducted. This transport occurred at least one hour prior to the onset of any behavioral testing.
  • each rat was placed in a fear conditioning box (MedAssociates; St. Albans, VT) scented with Pine-Sol (1%) for 250 sec total.
  • the rats had 3 minutes to explore the novel environment before tone (10 seconds, 85 dB)-shock (2 seconds, 0.35mA; coterminating with the tone) pairings [20 second intertrial intervals (ITIs)] were administered.
  • Ton extinction the rats were returned to the fear conditioning context for a total of 10 minutes.
  • tone extinction was administered by placing the rats in the fear conditioning boxes with an altered context.
  • White Plexiglas inserts were used to obscure the back and side wails and cover the grid floor.
  • each rat was tested as above, but with the following changes.
  • rats On the fear conditioning day, rats were exposed to four tone-shock pairings with a 60 second ⁇ (460 seconds total time).
  • For context extinction rats were returned to the conditioning context for 12 minutes total.
  • For tone extinction rats were exposed to twelve tones (10 seconds, 85 dB) for 960 seconds total. Conditioning, context and tone extinction sessions were separated by 24 hours.
  • Infrared cameras frame rate: 30Hz
  • VideoFreeze software MedAssociates; St Albans, VT
  • Motor activity was measured using the "motion index”, a number generated by the VideoFreeze software, which corresponds roughly to the change in grayscale values across the image pixels; a higher motion index indicates greater movement. Freezing was measured by computing the number of observations below a threshold motion index and converting this number to a percentage of all observations for the period of interest. The threshold defined the value of the motion index below which only motor activity related to breathing was observed.
  • Risk assessment behavior was defined as periods (>1 second duration) when a rat's body was immobile, but the head was moving. This behavior was quantified by an experienced observer, who watched the videos, blinded to the ghrelin level of the rat, and scored risk assessment on a second-by-second basis for the ten minute long-term auditory fear recall test. Risk assessment behavior was scored twice for each rat. Hormone Assays
  • Corticosterone and acylated-ghrelin levels were measured with commercial ELISA kits.
  • acylated ghrelin undiluted, acidified samples were processed according to the
  • biotinylated ghrelin was used to visualize ghrelin binding sites 11 in brain sections containing the BLA.
  • Anesthetized (Isoflurane; 3%) rats were transcardially perfused with ice-cold saline, followed by an ice-cold fixative containing 4% paraformaldehyde (PBS), pH 7.4. Brains were immediately removed and post-fixed in the same fixative for 2-16 hours. The brains were then transferred to 30% sucrose in 0.1M PBS. After several days, brains were cryosectioned into 30 ⁇ sections. Sections containing the BLA were mounted on gelatinized slides, dried at 4°C for 1-2 hours, and subsequently stored at -80°C until staining.
  • PBS paraformaldehyde
  • Sections were defrosted for 5 minutes. A wax boundary was drawn around the slices to minimize loss of liquid during the procedure.
  • Slices were washed twice in lx PBS in a tub on a shaker (5 minutes/wash). Sections were permeabilized in 0.25% Triton X in lx PBS for 15 min. Sections were then washed in lx PBS (3 times, 5 minutes/wash). Two drops of Reagent A (Strep tavidin) from the Endogenous Biotin Blocking Kit (Invitrogen Corporation; Grand Island, NY) were added per brain slice and left to incubate for 1 hour at room temperature. Sections were washed in lx PBS (3 times, 5 minutes/wash).
  • Fluorescence in situ hybridization staining was carried out to visualize GHSRla mRNA and GAD67 mRNA in the BLA using the QuantiGene ViewRNA ISH Tissue 2-Plex kit (Affymetrix; Santa Clara, CA) and staining procedures were performed according to the manufacturer's protocol.
  • Tissue sections were first dehydrated using increasing concentration of ethanol (50%, 70% and 100%) and then baked at 60°C for 30 minutes. The sections were then treated with Proteinase solution at 40°C for 40 minutes and hybridized for 2 hours at 40°C with custom- designed QuantiGene ViewRNA probes that are complement to GHSRla and GAD67. Unbound probes were washed out with Wash buffer and the bounded probes were then hybridized with Pre Amp solution for 25 minutes at 40° C, followed by Amp solution for 15 minutes at 40° C.
  • LP Two Label Probes (LP), that are conjugated to alkaline phosphatase (AP), were used to visualize the hybridization, of which the GHSRla was visualized by LP-AP-type 1 that reacted with Fast Red Substrate to deliver Cy3 fluorescence, whereas GAD67 by LP-AP-type 6 that reacted with Fast Blue Substrate to deliver Cy5 fluorescence.
  • Sections were counterstained with Gill's Hematoxylin (Sigma- Aldrich; St. Louis, MO) for the anatomical localization of amygdala nuclei, and with DAPI to label the nuclei. Slides were then mounted in Ultramount mounting medium (DAKO; Carpinteria, CA).
  • DAKO Ultramount mounting medium
  • each rat was returned to its home cage in a holding room. Each rat had 200g of chow placed in the food hopper. Food was quickly weighed and returned 30 minutes, I hour, 2 hours, and 3 hours after fear conditioning ended. Three days after fear recall testing (five days after fear conditioning), food consumption was measured during the same time points within the day, but while the rats were undisturbed in their home cages in the vivarium.
  • Multi-channel florescent images were acquired from brain sections containing the BLA to measure ghrelin binding and mRNA expression of GHSR and GAD67. Brain slices were imaged using a 20x objective on a Zeiss LSM 700 confocal laser scanning microscope coupled with Zen imaging software. Images of the left and right BLA were obtained based on the structure and coordinates of these regions from standard rat brain atlas 48. One animal was excluded from all analysis because the BLA could not be identified with confidence.
  • Fluorescent microscopy images were acquired using Zeiss Axio Vision software (Carl Zeiss Microimaging, Inc., Thornwood, NY) interfaced with a Zeiss Axio Observer Al fluorescence microscope with an AxioCam MRm camera. Images were all captured using a 63 x objective from amygdala nuclei according to a brain atlas 48. Two or three images (142 ⁇ X 106.5 ⁇ ) were captured for each region from each section (5-6 sections matched for rostral- caudal position across the amygdala) from 3 rats. Images were exported as 8-bit TIFF files and nuclear expression of target mRNAs was quantified using ImageJ software (NIH, Bethesda,
  • the total number of all cells was quantified in each image.
  • the expression of target mRNAs was quantified by examining the expression of fluorescent grains immediately adjacent or overlapping with each nucleus.
  • GHSRla receptors were identified as red grains (using a CY3/TRITC filter);
  • GAD67-expressing cells were identified by green grains (CY5 filter, green).
  • the number of cells expressing both GHSRla and GAD67 was also identified. Percentages of cells expressing GAD67 were calculated by dividing the total number of GAD67+ cells per region over the total number of all DAPI+ nuclei per region.
  • percentages of cells expressing GHSRla were calculated by dividing the total numbers of GHSR1 cells by the total numbers of DAPI+ nuclei.
  • the percentage of GHSRla cells expressing GAD67 was calculated by dividing the total number of GHSRla+/GAD67+ cells by the total number of GHSRla+ cells.
  • conditional freezing was expressed as the percentage of time spent freezing, a probability estimate amenable to analysis with parametric statistics. These estimates of freezing, as well as hormone levels and data related to food consumption and body weight, were analyzed using ANOVA. Post hoc Fisher's PLSD tests were performed after a significant omnibus -ratio.
  • the Lasso (least absolute shrinkage and selection operator) method 50 is a technique for estimating linear models that penalizes overfitting, and that tends to set some coefficients equal to zero. The Lasso method can thus be used for model selection by retaining the nonzero coefficients in a subsequent linear regression model.
  • ghrelin binding For ghrelin binding, a one-way ANOVA was used to determine whether ghrelin binding differed between stress-exposed and control rats. All statistical tests were computed using per- animal averages of each measure.
  • FIG. 1A auditory Pavlovian fear conditioning
  • Thy 1 -expressing neurons in the basolateral amygdala may mediate fear inhibition. J Neurosci 2013; 33(25): 10396-10404.
  • GH growth hormone
  • Articles such as “a,” “an,” and “the,” as used herein, may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a 30 given product or process unless indicated to the contrary or otherwise evident from the context.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the claims or from relevant portions of the description is introduced into another claim or another portion of the description.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • the claims recite a composition, it is to be understood that methods of using the composition for any of the purposes disclosed herein are included, and methods of making the composition according to any of the methods of making disclosed herein or other methods known in the art are included, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise.
  • any particular embodiment of the present invention may be explicitly excluded from any one or more of the claims. Where ranges are given, any value within the range may explicitly be excluded from any one or more of the claims. Any embodiment, element, feature, application, or aspect of the compositions and/or methods of the invention, can be excluded from any one or more claims. For purposes of brevity, all of the embodiments in which one or more elements, features, purposes, or aspects is excluded are not set forth explicitly herein.

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Abstract

L'invention concerne des procédés de traitement de maladies psychiatriques sensibles au stress dues à un traumatisme chez un sujet par augmentation de la signalisation de la ghréline dans le complexe basolatéral de l'amygdale du sujet. L'invention concerne également des procédés pour traiter une résistance à la ghréline.
PCT/US2016/019297 2015-02-24 2016-02-24 Utilisation de ghréline ou d'agonistes fonctionnels des récepteurs de la ghréline pour prévenir et traiter une maladie psychiatrique sensible au stress WO2016138099A1 (fr)

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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10039813B2 (en) 2012-02-07 2018-08-07 Massachusetts Institute Of Technology Use of antagonists of ghrelin or ghrelin receptor to prevent or treat stress-sensitive psychiatric illness
US9724396B2 (en) 2013-03-15 2017-08-08 Massachusetts Institute Of Technology Use of antagonists of growth hormone or growth hormone receptor to prevent or treat stress-sensitive psychiatric illness
WO2019008554A1 (fr) * 2017-07-06 2019-01-10 Conte Anthony Méthode pour le traitement oral et la prévention d'une maladie cardiovasculaire
US10288629B1 (en) * 2017-12-19 2019-05-14 Aeterna Zentaris, Inc. Method of assessing growth hormone deficiency in humans by a macimorelin containing composition
WO2021067819A1 (fr) * 2019-10-04 2021-04-08 Allergan Gi Corp. Compositions pour une administration par voie intranasale de relamoréline

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013119800A1 (fr) * 2012-02-07 2013-08-15 Massachusetts Institute Of Technology Utilisation d'antagonistes de ghréline ou de récepteur de ghréline pour prévenir ou traiter une maladie psychiatrique sensible au stress

Family Cites Families (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4857637A (en) 1986-05-07 1989-08-15 Genentech, Inc. Methods and compositions for immunologically modulating growth hormone receptor activity
US4997815A (en) 1988-11-01 1991-03-05 Children's Hospital Medical Center Of Northern California Method for augmenting fetal hemoglobin by treatment with activin and/or inhibin
US5439939A (en) 1992-03-17 1995-08-08 Children's Hospital Medical Center Of Northern California Pharmaceutical compositions and methods using isobutyramide for treating betaglobin disorders
WO1997011178A1 (fr) 1995-09-21 1997-03-27 Genentech, Inc. Variants de l'hormone de croissance humaine
WO1997041878A1 (fr) 1996-05-07 1997-11-13 Merck & Co., Inc. Traitement de troubles de l'humeur, a l'aide d'un secretagogue d'hormone de croissance
CZ20014534A3 (cs) 1999-06-25 2002-06-12 Societe De Conseils De Recherches Et D´Applic Atio Peptid, farmaceutický prostředek a způsob
UA77650C2 (en) 1999-12-06 2007-01-15 Lundbeck & Co As H Use of serotonin reuptake inhibitor in combination with deramcyclane
US20030211967A1 (en) 2001-05-07 2003-11-13 Bryant Henry Uhlman Method for selectively inhibiting ghrelin action
MXPA03000738A (es) 2000-07-24 2003-06-04 Ardana Bioscience Ltd Antagonistas de grelina.
US7666833B2 (en) 2001-12-18 2010-02-23 Alizé Pharma SAS Pharmaceutical compositions comprising unacylated ghrelin and therapeutical uses thereof
CA2483330C (fr) 2002-04-22 2013-09-03 Greenville Hospital System Ligands multimeres a stabilite renforcee
WO2003092725A1 (fr) 2002-05-03 2003-11-13 Metabolic Pharmaceuticals Limited Procede permettant de maitriser la depression a l'aide d'un fragment d'hormone de croissance (gh) a terminaison c
JP2006506968A (ja) 2002-07-03 2006-03-02 メルク　エンド　カムパニー　インコーポレーテッド アグーチ関連蛋白質欠損細胞、非ヒトトランスジェニック動物及びエネルギー代謝を調節する化合物の選択方法
TWI331922B (en) 2002-08-09 2010-10-21 Ipsen Pharma Sas Growth hormone releasing peptides
MY139563A (en) 2002-09-04 2009-10-30 Bristol Myers Squibb Co Heterocyclic aromatic compounds useful as growth hormone secretagogues
WO2004056869A1 (fr) 2002-12-20 2004-07-08 7Tm Pharma A/S Agoniste inverse du recepteur de la ghreline pour reguler des comportements alimentaires
GB0300571D0 (en) 2003-01-10 2003-02-12 Imp College Innovations Ltd Modification of feeding behaviour
WO2004084943A1 (fr) 2003-03-19 2004-10-07 Beth Israel Deaconess Medical Center, Inc Utilisation d'antagonistes de la ghrelin ou du recepteur de la ghrelin pour traiter l'inflammation intestinale
US7491695B2 (en) 2003-06-18 2009-02-17 Tranzyme Pharma Inc. Methods of using macrocyclic modulators of the ghrelin receptor
US7476653B2 (en) 2003-06-18 2009-01-13 Tranzyme Pharma, Inc. Macrocyclic modulators of the ghrelin receptor
US20070275877A1 (en) 2003-08-29 2007-11-29 Amylin Pharmaceuticals, Inc. Methods for Treating or Ameliorating Ghrelin-Associated Diseases and Disorders
US20050070712A1 (en) 2003-09-26 2005-03-31 Christi Kosogof Pyrimidine derivatives as ghrelin receptor modulators
MXPA06005038A (es) 2003-11-04 2007-12-12 Elixir Pharmaceuticals Inc Compuestos terapeuticos y usos de los mismos.
KR20060128924A (ko) 2004-01-20 2006-12-14 사이토스 바이오테크놀로지 아게 그레린-담체 접합체
WO2005097830A2 (fr) 2004-04-07 2005-10-20 Aditech Pharma Ab Utilisations d'elements de liaison isoles capables de reduire l'activite biologique de composes secretagogues
WO2005112903A2 (fr) 2004-05-14 2005-12-01 Novo Nordisk A/S Utilisation d'antagonistes de la ghrelin pour le traitement de certaines maladies du systeme nerveux central
US20070237775A1 (en) 2004-07-14 2007-10-11 Eli Lilly And Company Anti-Ghrelin Antibodies
KR101380200B1 (ko) 2004-08-12 2014-04-01 헬신 세라퓨틱스 (유.에스.) 인크. 성장 호르몬 분비촉진제를 이용하여 위장관계의 운동성을촉진하는 방법
US8039456B2 (en) 2004-08-12 2011-10-18 Helsinn Therapeutics (U.S.), Inc. Method of stimulating the motility of the gastrointestinal system using ipamorelin
EP1781311A4 (fr) 2004-08-18 2010-02-17 Elixir Pharmaceuticals Inc Secretagogues d'hormone de croissance
WO2006091381A1 (fr) 2005-02-23 2006-08-31 Eli Lilly And Company Anticorps anti-ghreline humanises
US20060293370A1 (en) 2005-06-10 2006-12-28 Saunders Jeffrey O Sulfonamide compounds and uses thereof
US20090275648A1 (en) 2005-06-13 2009-11-05 Fraser Graeme L Macrocyclic ghrelin receptor antagonists and inverse agonists and methods of using the same
JP4879265B2 (ja) 2005-07-22 2012-02-22 イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ 成長ホルモン分泌促進薬
EP1757290A1 (fr) 2005-08-16 2007-02-28 Zentaris GmbH Derivés de triazole comme ligands du recepteur de l'hormone de croissance
CA2625920C (fr) 2005-09-28 2014-12-23 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R Analogues de la ghreline
WO2007092023A1 (fr) 2006-02-11 2007-08-16 Boston Biomedical Research Institute Compositions et procedes de liaison ou de desactivation de ghreline
WO2007101021A2 (fr) 2006-02-22 2007-09-07 Eli Lilly And Company Anticorps anti-ghrelin humanisés
WO2007106385A2 (fr) 2006-03-10 2007-09-20 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Utilisation d'un agoniste de la ghréline pour améliorer les effets cataboliques d'un traitement aux glucocorticoïdes
CA2647815C (fr) 2006-03-28 2021-11-23 Liat Mintz Utilisation d'une variante d'epissage de la ghreline pour traiter l'hypercholesterolemie ou un taux de cholesterol eleve ou une complication du taux de cholesterol eleve ou la lipemie ou une complication de la lipemie ou une maladie cardiaque coronarienne ou la prise en charge du poids ou le diabete ou l'hyperglycemie
WO2007127457A2 (fr) 2006-04-28 2007-11-08 The Administrators Of The Tulane Educational Fund Antagonistes de récepteur de sécrétagogue d'hormone de croissance/de peptide libérant une hormone de croissance/de ghréline et utilisations de ceux-ci
ES2532848T3 (es) 2006-07-04 2015-04-01 Combigene Ab Uso de secuencias de ácidos nucleicos para el tratamiento de enfermedades neurológicas y psiquiátricas, vectores y composiciones
JP2009542809A (ja) 2006-07-12 2009-12-03 メルク エンド カムパニー インコーポレーテッド グレリン受容体アンタゴニストとしての置換ピラゾール
WO2008016911A2 (fr) 2006-07-31 2008-02-07 Oregon Health & Science University Réplication de signalisation de la mélatonine chez un fœtus, un nouveau-né ou un nourrisson
EP2046376B1 (fr) 2006-08-01 2018-08-01 The Scripps Research Institute Vaccins et procédés pour contrôler l'adiposité
US20080119540A1 (en) 2006-11-21 2008-05-22 D.N. Halgren Method of using oral lipase inhibitors to reduce plasma ghrelin and to prevent weight regain
RU2459831C2 (ru) 2006-09-27 2012-08-27 Ипсен Фарма С.А.С. Аналоги грелина с замещением на n-конце
US8933105B2 (en) 2007-02-28 2015-01-13 Takeda Pharmaceutical Company Limited Pyrrole compounds
TWI429436B (zh) 2007-04-10 2014-03-11 Helsinn Therapeutics Us Inc 使用生長激素促泌素治療或預防嘔吐之方法
US8318664B2 (en) 2007-05-31 2012-11-27 Alize Pharma Sas Unacylated ghrelin fragments as therapeutic agent in the treatment of obesity
GB0710865D0 (en) 2007-06-06 2007-07-18 Glaxo Group Ltd Novel compounds
GB0717985D0 (en) 2007-07-20 2007-10-24 Asterion Ltd Growth hormone fusion proteins
EP2175724A4 (fr) 2007-08-01 2010-09-15 Medivation Neurology Inc Procédés et compositions destinés au traitement de la schizophrénie par thérapie de combinaison d'antipsychotiques
PE20090709A1 (es) 2007-09-28 2009-07-15 Takeda Pharmaceutical Compuestos heterociclico de 5 miembros
US8969387B2 (en) 2008-08-27 2015-03-03 Takeda Pharmaceutical Company Limited Pyrrole compounds
US8013015B2 (en) 2008-10-02 2011-09-06 Board Of Regents, The University Of Texas System Small molecule inhibitors of ghrelin O-acyltransferase
US8772229B2 (en) 2008-10-03 2014-07-08 The Johns Hopkins University Methods for synthesis and uses of inhibitors of ghrelin O-acyltransferase as potential therapeutic agents for obesity and diabetes
US20120088747A1 (en) 2008-10-30 2012-04-12 Saunders Jeffrey O Sulfonamide containing compounds and uses thereof
US8309530B2 (en) 2009-02-04 2012-11-13 Washington State University Compositions and methods for modulating ghrelin-mediated conditions
UA105657C2 (uk) 2009-02-27 2014-06-10 Хелсінн Терапьютікс (Ю.Ес.), Інк. Поліпшені способи лікування мігрені на основі анамореліну
BRPI1014522B8 (pt) 2009-04-27 2021-05-25 Novartis Ag anticorpo anti-actriib ou fragmento funcional, processo de produção dos mesmos, composição farmacêutica e usos
GB0907350D0 (en) 2009-04-29 2009-06-10 Myotec Therapeutics Ltd Methods
US8883721B2 (en) 2009-05-12 2014-11-11 Mcgill University Methods of inhibiting the ghrelin/growth hormone secretatogue receptor pathway and uses thereof
CA2778990A1 (fr) 2009-10-30 2011-05-05 Tranzyme Pharma, Inc. Antagonistes et agonistes inverses macrocycliques du recepteur de la ghreline et leurs methodes d'utilisation
US9365651B2 (en) 2011-07-01 2016-06-14 Novartis Ag Method for treating metabolic disorders by administration of an anti-ActRIIB antibody
KR20140146192A (ko) 2012-04-14 2014-12-24 인트라-셀룰라 써래피스, 인코퍼레이티드. 유기 화합물
US10012656B2 (en) 2012-08-13 2018-07-03 Otago Innovation Limited NT-proCNP as a biomarker of vascular disorders and pregnancy complication
NZ707174A (en) 2012-09-27 2018-10-26 Aratana Therapeutics Inc Compositions and methods of use of an inappetance-controlling compound
US20140287997A1 (en) 2013-03-15 2014-09-25 Massachusetts Institute Of Technology Use of growth hormone or growth hormone receptor agonists to prevent or treat stress-sensitive psychiatric illness
US9724396B2 (en) 2013-03-15 2017-08-08 Massachusetts Institute Of Technology Use of antagonists of growth hormone or growth hormone receptor to prevent or treat stress-sensitive psychiatric illness
US20160106821A1 (en) 2014-10-20 2016-04-21 Massachusetts Institute Of Technology Functional ghrelin receptor antagonism during pregnancy to prevent stress-associated mental illness in offspring and mothers
US20170007618A1 (en) 2015-06-17 2017-01-12 Massachusetts Institute Of Technology Serotonin 2c receptor antagonists to prevent and treat stress-related trauma disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013119800A1 (fr) * 2012-02-07 2013-08-15 Massachusetts Institute Of Technology Utilisation d'antagonistes de ghréline ou de récepteur de ghréline pour prévenir ou traiter une maladie psychiatrique sensible au stress

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CARVAJAL P. ET AL.: "Central ghrelin increases anxiety in the Open Field test and impairs retention memory in a passive avoidance task in neonatal chicks", NEUROBIOLOGY OF LEARNING AND MEMORY, vol. 91, 2009, pages 402 - 407, XP026072839, DOI: doi:10.1016/j.nlm.2008.12.008 *
LUTTER M. ET AL.: "The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress", NATURE NEUROSCIENCE, vol. 11, no. 7, 2008, pages 752 - 753, XP008155709, DOI: doi:doi:10.1038/nn.2139 *
MEYER R. ET AL.: "A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear", MOLECULAR PSYCHIATRY, vol. 19, no. 12, 2014, pages 1284 - 1294 *
SPENCER S. ET AL.: "Ghrelin Regulates the Hypothalamic-Pituitary-Adrenal Axis and Restricts Anxiety After Acute Stress", BIOLOGICAL PSYCHIATRY, vol. 72, 2012, pages 457 - 465 *

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